Obesity is a major health issue. The fundamental problem in obesity is a disordered regulation of energy intake (EI) and/or energy expenditure (EE), which is largely controlled by the brain. Recently, several lines of evidence from our laboratory and others suggest that brain derived neurotrophic factor (BDNF) plays an important role in energy balance. BDNF in the hypothalamic paraventricular nucleus (PVN) and ventromedial nucleus (VMH) shows delayed inhibitory effects on EI and immediate stimulatory effects on EE and resting metabolic rate (RMR). We also found that BDNF immediately increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), suggesting that BDNF induces EE elevation via activation of BAT UCP1. Our preliminary data on potential mechanisms of BDNF effects indicate that: 1) blockade of BDNF binding to TrkB receptor attenuates BDNF-inhibited feeding; 2) blockade of CRH receptor (CRHR) signaling attenuates BDNF-inhibited feeding; and 3) chronic (14 d) injection of BDNF reduces feeding and body weight long-term and increases proliferation of newborn cells in the region. Here we propose 4 hypotheses: 1) BDNF exerts effects on energy metabolism through binding to its receptor TrkB; 2) BDNF effects on energy balance are mediated by CRHR signaling pathway; 3) BDNF prevents high fat diet (HFD) induced obesity; and 4) Chronic BDNF induces proliferation of newborn neurons that impact energy metabolism. The proposal has following 4 specific aims focusing on the VMH site: Aim I. Determine role of BDNF-TrkB signaling in BDNF effects on energy metabolism Does blockade of BDNF-TrkB signaling block BDNF-induced: 1) reduction of feeding and body weight gain, 2) increases in EE, and 3) elevation of UCP1 in BAT? Aim II. Determine role of CRHR signaling in BDNF effects on energy metabolism. Does blockade of CRHR block BDNF-induced: 1) reductions in feeding and body weight, 2) increases in EE, and 3) elevation of UCP1 in BAT? Aim III. Determine effect of BDNF on high fat diet-induced obesity 1) Does chronic BDNF prevent high-fat diet-induced obesity? Aim IV. Determine BDNF effects on neurogenesis and energy metabolism. 1) Does chronic BDNF induce long-term effects on energy balance and neurogenesis? 2) Does blockade of BDNF-induced neurogenesis block BDNF-induced anorexia? 3) Are BDNF-induced newborn neurons responsive to neuropeptides (CRH, leptin, and melanocortin) important to energy metabolism? The proposed studies of BDNF will provide additional information important to our efforts to combat obesity and its associated clinical problems, and thus will benefit a great percentage of obese patients and the public. PUBLIC HEALTH RELEVANCE Obesity is a major health problem affecting a large proportion of the U.S. population, and the fundamental issue of obesity is a regulation disorder of eating and energy output, which is largely controlled by the central nervous system. It is crucial to understand how neural pathways regulate body weight and find approaches to prevent and treat obesity. The proposed studies will determine the process by which a brain chemical, BDNF reduces feeding and increases energy output, which will enable researchers to more informatively focus efforts to combat obesity and its associated clinical problems.